Understanding the Roles of REG? in Anaplastic Thyroid Cancer Progression (Summary) Anaplastic thyroid cancer (ATC) is the most advanced and aggressive thyroid cancer and is the least likely to respond to treatment. Genetically, alteration of p53, p21Waf/Cip1 as well as other cell cycle regulators may be responsible for the transformation of well-differentiated thyroid cancer cells to ATC. In addition, oncogenic conversion of B-RAF occurs in ~44% of papillary thyroid carcinomas and 24% of anaplastic thyroid carcinomas. However, the carcinogenesis of ATC is still poorly understood and novel, efficient, therapeutic approaches have yet to be developed. We have provided evidence that p21 is a direct target of REG?-proteasome and that REG? is involved in promoting cell growth and cell cycle regulation. Furthermore, we found a series of other cell cycle regulators are also targets of REG?-proteasome. Preliminary studies indicate an abnormally high expression of REG?, non-detectable p21 level in anaplastic thyroid cancer samples, and potential regulation of REG? activity by B-RAF/MAP3K mediated phosphorylation. In this proposal, we hypothesize that a high level of REG? and depletion/reduction of p21 along with other cell cycle regulators may be responsible for ATC progression and that the regulation of REG? by B-RAF/MAP3K signaling may be a novel mechanism in ATC carcinogenesis. To test our hypothesis, we propose to further characterize protein levels of REG?, p21, p53, and the other cell cycle regulators targeted by REG? in ATC tissue array. We also propose to examine the impact of REG? and its target protein on carcinogenesis and biological properties in thyroid cancer cell lines. Finally, we will investigate the molecular details of phosphorylation of REG? by B-RAF/MAP3K kinases in ATC progression. Considering the roles of B-RAF in malignant thyroid cancer and colorectal cancer and "coincidental" involvement of REG? in these cancers, this proposal seeks to pioneer a novel study that may address some fundamental questions in malignant cancer progression and may provide further insight into the clinical application of cancer control. PUBLIC HEALTH RELEVANCE: The proteasome activator, REG?, has been known to express highly in two malignant cancers, thyroid cancer and colorectal cancer, and may play an important role in the progression of these cancers. This project is to understand the tumorigenic role of REG? in anaplastic thyroid cancer, the most malignant thyroid cancer, and results from this study will be of direct relevance to medicine. Considering proteasome inhibitor has emerged as a truly intriguing anticancer agent, this project may provide the basis for the development of novel therapeutics for human cancers.